The theme of this project is the evaluation of newly available compounds modulating brain monoamine systems as potential treatments for cocaine or methamphetamine dependence. The selected medications have not yet been evaluated in patients with stimulant dependence, so assessment of their effects in this population will provide critical new information for the addiction research field. The proposed medications for cocaine dependence are RTI-336 and JD-Tic. RTI-336 is a selective inhibitor of the dopamine transporter (DAT) that reduces cocaine self-administration by rats and monkeys. JD-Tic is a long-acting, orally active kappa opioid antagonist that blocks stress-induced reinstatement of cocaine-seeking behavior in rats. Kappa opioid receptors are up-regulated in cocaine users, indicating that kappa opioid systems may play an important role in cocaine relapse. The proposed medications for methamphetamine dependence are YPK10A and SYN-115. YPK10A, previously known as R228060, has negligible activity at monoamine transporters and receptors but has a stimulant-like behavioral profile, suggesting that it may have a novel mechanism of action. YPK10A reduces cocaine self-administration in rats, suggesting that it has potential efficacy for treating stimulant dependence. SYN-115 is a selective adenosine-2a (A2a) receptor antagonist that reduces the rewarding effects of cocaine in the rat conditioned place preference test, probably by enhancing dopaminergic neurotransmission. Consistent with this, an A2a antagonist is undergoing late phase clinical trials for the treatment of Parkinson's disease. Overall, the planned phase I studies in this project will provide critical information regarding the safety and potential efficacy of these compounds as treatments for cocaine or methamphetamine dependence. We will use this information to design outpatient trials to evaluate medications as treatments for cocaine or methamphetamine dependence. In addition, we will use the results from these trials to define the phenotypes and to develop endophenotypes that will be used in the pharmacogenetic core to identify genetic factors associated with these variables.